Two teams have reported the development of new anti-HIV compounds that target a highly conserved pocket in the viral coat protein gp41. In one study (Cell 99, 103–115, 1999), scientists at MIT (Cambridge, MA) began by synthesizing the pocket segment of gp41 from d-amino acids, creating a mirror image of the natural pocket. Using this d-peptide as bait, they screened a phage expression library and identified l-peptides that bind specifically to the synthetic pocket. d-peptide versions of these were then synthesized and shown to both bind specifically to the normal gp41 pocket and prevent HIV entry into cells. As d-peptides do not occur naturally and are resistant to proteolytic enzymes, optimized versions of the new pocket-binding peptides might be useful as orally delivered drugs. According to Howard Hughes Investigator Peter Kim, senior author on the study, a non-exclusive license on the technique is currently being offered. A more traditional approach using a rationally designed biased combinatorial library has been employed by researchers at the Howard Hughes Medical Institute, Harvard Medical School (Boston, MA), to identify small molecules that also bind the gp41 pocket and inhibit HIV entry (Nat. Struct. Biol. 6, 953–959, 1999).